Download Alcohol Withdrawal Syndrome - American College of Medical

Alcohol Withdrawal Syndrome
Treatment options beyond benzodiazepines
José R. Maldonado, M.D., FAPM, FACFE
Associate Professor of Psychiatry, Medicine, Surgery & Law
Scholar, Center for Biomedical Ethics
Stanford University School of Medicine
Stanford University School of Law
Chief, Medical & Forensic Psychiatry Section
Medical Director, Psychosomatic Medicine Service
Stanford University Medical Center
[email protected]
American College of Medical Toxicology
ALCOHOL ABUSE ACADEMY
Disclosure:
José Maldonado, MD
With respect to this presentation,
there has been no relevant (direct or indirect)
financial relationship between
Dr. Maldonado (and/or spouse)
and any for-profit company in the past 10 years
which could be considered a conflict of interest.
AUD & Psychosomatic Medicine
•  Hospital Setting
–  In a study performed at a major university hospital, 30% of
patients admitted to the medical units (for reasons other
than alcohol abuse or withdrawal) experienced alcohol
withdrawal symptoms requiring pharmacologic treatment
(Maldonado 2000).
–  According to a nationwide survey of the Veterans Affairs
system, 42% of all veteran inpatients required medications
to aid detoxification from alcohol (Tracey 2004).
–  Of patients presenting for alcohol detoxification up to 73%
will develop significant symptoms of alcohol withdrawal
requiring pharmacologic intervention (Wartenberg 1990, Saitz
1997).
–  Almost half of all trauma beds are occupied by patients
who were injured while under the influence of alcohol (Herve
et al 1986; Gentilello et al 1995; Soderstrom et al 1992; Spies et al 1996).
* All based in USA data
AUD & Psychosomatic Medicine
•  Hospital Setting
–  Chronic alcohol misuse is more common in surgical
patients (e.g., up to 43% in EENT) than in psychiatric (30%)
or neurological (19%) patients. 1
–  In addition to the life-threatening complications of alcohol
withdrawal syndrome (AWS):
•  In General Medicine: the rate of morbidity and mortality due to
infections, cardiopulmonary insufficiency, or bleeding
disorders is 2 to 4 times greater in chronic alcoholics. 2-7
•  In Surgical Services: 8-12
!  2 – 3X the morbidity of pts who drink <2/d
• 
• 
• 
• 
More 2ry surgeries
50% longer hospital stay
Poorer 3-month outcome
Complications: infections, bleeding problems, cardiopulmonary
insufficiency.
1. Moore et al 1989; 2. Herve et al 1986; 3. Jensen et al 1988; 4. Jurkovich et al 1993; 5-7. Spies et al 1996a,b, 1997;
8. Felding et al 1992; 9. Sonne et al 1992; 10-12. Tonnesen et al 1988, 1992, 1999.
Pharmacology of Ethanol
•  Complete absorption: 2 – 6 hrs
•  Most foods retard absorption
•  90 – 98% is hepatically metabolized via oxidation at
a relatively slow rate following zero-order kinetics
(i.e., independent of time and concentration)
•  Average rate of metabolism:
!  About 20 mg/dl/hr or
!  Roughly 1 oz of hard liquor/1.5 hrs
!  A rule of thumb is that the average rate of fall is 0.02 g% per hour which
coincidentally is also the level to which the blood alcohol rises after a single
standard (10 g) drink.
!  ~2% escapes oxidation and is excreted via kidneys and lungs
•  Prolonged use of alcohol is associated with the
accumulation of protein and fat in the liver, leading to
various stages of hepatic disease culminating in cirrhosis
Effects of Acute Ethanol in
Non-Habituated Individuals
Death *
0.6
600mg/100dl
0.5
alcoholic coma
500mg/100dl
0.4
400mg/100dl
0.3
300mg/100dl
0.2
anesthesia,
unconsciousness
stupor, hypothermia,
amnesia, stage I anesthesia
confusion and ↓ consciousness
200mg/100dl
0.1
100mg/100dl
0.05
50mg/100dl
ataxia, prolonged reaction time,
poor coordination, mental impairment *
0.08=80mg/100dl Legal driving limit in most states
mild coordination problems; changes in mood, personality and behavior
Alcohol Withdrawal Syndromes
S
Major Withdrawal (DT’s)
y
m
p Seizures
confusion
t
o
m
Hallucinosis
I
n
t
e
n
s
i
t
y
Tremors, irritability & insomnia
Minor Withdrawal
0
1
2
3
4
5
6
7
8
Days
9
10
11
12
13
14
Maldonado et al, 2009
Alcohol Withdrawal Treatment
Alcohol Replacement
Drawbacks:
•  There is no scientific evidence
demonstrating the utility of alcohol
use in the management of alcohol
withdrawal.
•  ↑ caloric content, lack of proteins and
nutrients
•  Unfavorable TD/ED ratio. Difficult to
titrate
•  Short T1/2
•  Perpetuates medical problems
•  Gastritis if given PO
•  Poor clinical utility
•  Only delays ultimate goal
• 
IV ETOH vs IV-Benzodiazepine
studies have demonstrated no
superior prophylactic effect; in fact,
in a SICU study, more patients
failed to be under adequate control
in the IV-ETOH group
(Weinberg et al, 2008)
•  There is little evidence from
controlled studies to support this
practice over standard treatments,
and there are concerns regarding
the efficacy, pharmacokinetic
profile and narrow therapeutic
index of ethanol, particularly in
critically ill patients.
(Hodges & Mazur 2004)
•  In order to achieve adequate
symptom control, IV ethanol had
to be infused (for IV ethanol) or
alcoholic beverages given (for PO
alcohol consumption) to achieve a
BAL = 0.08 = 80mg/100d [which is
equal to legal intoxication levels in
the USA].
•  There are no adequate titration
protocols.
(Dissanaike et all, 2006)
Alcohol Withdrawal Treatment
Barbiturates
•  Good cross-coverage to the
CNS-D Rx.
•  Effective in decreasing the
incidence and rate of tremors
and seizures in AWS.
•  Long T1/2, provides good selftaper
•  Are available PO, IM, or IV
•  Drawbacks:
–  Unfavorable TD/ED ratio
–  Compared with long acting BZD, are no better, but do
have more side effects
Medications Commonly Used for
Antianxiety/Hypnotic/Sedative Purposes
0.25
*= has no active metabolites. I = intermediate; R = rapid. U-dose = [ ] = usual dose. φ=metabolized
by glucuronidation (usually unaffected by hepatic failure); all other agents require oxidative
metabolism .∝=good SL absorption.
Jose R. Maldonado, MD 1997, 1999
Stanford University Study
“Prospective Comparison of Lorazepam versus Diazepam
in the Treatment of Alcohol Withdrawal”
• 
• 
• 
Design: Prospective, randomized, case-control study @ SHC & PAVA
Loading method
–  Requires the use of a long acting agent (e.g., diazepam,
chlordiazepoxide)
–  Given every hour until sedation is achieved or significant
improvement on the withdrawal scale score (e.g. CIWA-Ar)
–  Postulate that T ½ will allow for Rx self-tapering, thus easier
administration and avoidance of under-sedation.
–  Critics remark on the possibility of over-sedation, leading to possible
respiratory depression and prolonged hospitalizations.
Symptom-triggered approach
–  Promotes the use of short acting agents (e.g., lorazepam)
–  Administered based on threshold of withdrawal scale score
–  Postulate that avoidance of over-sedation may lead to faster
resolution of the symptoms and earlier discharge from the hospital
–  Critics highlight possible “break-through” withdrawal, need for
constant administration, development of benzodiazepine
dependence.
Maldonado et al, Gen Hosp Psychiatry. [Epub ahead of print]
Results
Results
Lorazepam
Diazepam
Total BZD Usage,
in diazepam equivalents
(mgs) (p >.05)
92.396
SD 103.47
103.75
SD 71.49
CIWA-Ar, Mean Rate of
Change (p >.05)
-3.62
SD 4.48
-4.56
SD 3.41
Systolic B P, Mean Rate of
Change (p >.05)
-2.73
SD 5.27
-2.35
SD 6.28
Maldonado et al, Gen Hosp Psychiatry. [Epub ahead of print]
Why are BZDPs not always the Best?
•  10/1: Pt involved on a fight- blow
to L eye- admitted to Dominican
Hosp @ 1500; reported LOC.
–  No record of BAL/Utox
–  HR 110-116; BP 138-146/88-92
–  Hx BAD.
•  10/1 @ 2100 transferred to SHC;
no BAL on adm.
•  10/2 @ 0300 BAL=71.4mg/100dl;
CAGE 4/4.
Day
BAL
HR
BP
70-80s
139-158
/68-77
101-1
43
130-150
s
/80-90s
10/3
107-1
51
127-169
/82-91
10/4
110-1
30
10/5
10/1
10/2
71.4mg
/100dl
O2 sat
MSE
BZDP
1mg-LOR
Restraints placed after became verbally
aggressive and took a swing at a nurse
14mg-LOR
30mg-DIA
100mg
Broke through his restraints and tore his Poseydue to desaturation had to receive Flumezanil
24mg-LOR
30mg-DIA
150mg
131-145
/80-90s
Started on clonidine 0.2mg TDS, but d/cd
within hrs p Psych consult. ativan 2mg IV prn
for HR>100, SBP>160, DBP>100, tremors,
chills hold for sedation (note he was already
sedated)
24mg-LOR
30mg-DIA
108-1
54
123-164
/73-95
C/L: 0.4mg clonidine patch, 0.5mg clonidine
PO that day, VPA 500, 1000, decreasign
quetiapine 1000 to 500, ativan CIWA >15
6mg-LOR
0-DIA
10/6
81-13
0
110/65-1
49/82
10/06/11 increased VPA to 2g. changed CIWA
trigger to 20.
0
10/7
85-13
0
129-142
/74-92
10/07/11 we recommended stopping quetiapine
completely and adding haldol 0.5mg BID, 2mg
qhs and 2mg q8 h prn extreme agitation (only
received once)
0
10/8
81-95
120-10s/
70s
10/08/11 out of restraints (placed 10/02/11). no
avitan since 10/5/11.
HR down to the 80s. sitting in a chair
0
10/9
76-83
116/66-1
35/73
88% on
4L
0
150mg
Alcohol Withdrawal Treatment
Alternative to Benzodiazepines
• 
• 
Benzodiazepines represent the standard of care for the treatment of AWS and Tx
prevention of alcohol withdrawal seizures and delirium tremens (Mayo-Smith, 1997)
Potential problems with the use of BZD:
I. 
BZD have abuse liability (Ciraulo et al., 1998). This is problematic in an outpatient
setting or when trying to discharge home a patient on moderate or high doses.
II.  Concurrent alcohol/benzodiazepine use: 29 – 76% (Busto et al 1991; Ciraulo et al
1988)
III.  BZD blunt cognition which might hamper early attempts at rehabilitation
counseling.
!  New evidence suggests that BZDP use may be associated with an increased risk of
dementia (de Gage et al BMJ 2012).
IV.  BZD have significant interactions with alcohol, opioids, and other CNSdepressant agents. If taken together, there can be additive respiratory
depression and cognitive impairment (Denaut et al 1974; Gross et al 1983).
V.  There are preclinical and clinical studies suggesting that BZD use may increase
craving, early relapse to alcohol use, and increased alcohol consumption (Longo
et al 2002; Malcolm et al., 2002; Poulos and Zack, 2004).
V.  Increased risk of developing BDZP-induced delirium; mostly due to it’s a-chol
activity.
Maldonado 2011, 2012; Pandharipande P, et al. J Trauma. 2008;65:34-41;
Pandharipande P, et al. Anesthesiol. 2006:104:21-26; Repper, Stern et al, Psychosomatics, 2008
Delirium Risk Factors
Insult
Electrolyte imbalance
Neurological
Deficiencies (nutritional)
Age & baseline Cognitive status
CNS depressant withdrawal
U-Tox (intoxication)
Trauma
Endocrine disturbance
Baseline
Cognitive
Functioning
Behavioral-Psychiatric
Rx & other toxins
Anemia, anoxia, hypoxia & Low
perfusion states
Infectious
Noxious stimuli (Pain)
Failure (organ)
Apache score (severity of illness)
Impairment (sensory)
Light, sleep & Circadian Rhythm
Uremia & other Metabolic Disorders
Restraints
Emergence delirium
Delirium Risk
Premorbid
State
•  > 5 Rx’s
•  Psychoactive agents
•  Anticholinergic potential
Lorazepam Dose, mg
The probability of transitioning to delirium increased
with the dose of lorazepam administered in the
previous 24 h. This incremental risk was large at low
doses and plateaued at around 20 mg/day.
Pandharipande et al 2006
Alcohol-Withdrawal Pathway at MGH
Results: Patient outcomes
(e.g., length of stay and the
incidence of delirium)
improved for those patients
who received benzodiazepines
within the range of the
pathway guidelines.
Repper, Stern et al, Psychosomatics, 2008
A Basic Pathoetiological Model of Delirium
Premorbid
State
Insult
Electrolyte imbalance
Neurological
Deficiencies (nutritional)
Age & baseline Cognitive status
CNS depressant withdrawal
U-Tox (intoxication)
Trauma
Endocrine disturbance
Baseline
Cognitive
Functioning
Behavioral-Psychiatric
Rx & other toxins
Anemia, anoxia, hypoxia & Low
Maldonado, Crit Care Clinic, 2008;24:789-856
The ‘‘neurotransmitter hypothesis’’
suggests that changes in neurotransmitter
concentration or receptor sensitivity (due
to decreased oxidative metabolism in the
brain causing cerebral dysfunction) may
underlie the different symptoms and
clinical presentations of delirium:
" Reduced availability of
!  acethylcholine ( Ach)
perfusion states
Infectious
Noxious stimuli (Pain)
" Excess release of:
Failure (organ)
Apache score (severity of illness)
Impairment (sensory)
Light, sleep & Circadian Rhythm
Uremia & other Metabolic Disorders
Restraints
Emergence delirium &
" Both decreased and increased activity in:
WD of CNS Depressant
!  dopamine (DA)
!  norepinephrine (NE)
!  glutamate (GLU)
!  serotonin (5HT)
!  histamine (H1&2)
!  gamma-aminobutyric acid (GABA)
A Basic Pathoetiological Model of Delirium
Maldonado, Crit Care Clinic, 2008;24:789-856
i.e., hypoxia
i.e., hyperthermia: for every
↑1C° fever ↑VO2 by 13%
Critical Illness
↑ O2 demand
↓ O2 supply
↓ O2 availability to brain tissue
ATP-ase pump failure
Na+ influx
↓ NAD:NADH ratio
ACh
(Siesjo ’84)
(Bauer ’82;
Koponen ’89;
Romano & Engel ’44;
Trzepacz ‘92)
(Gibson & Blass ’76;
Gibson et al ‘81)
K+ outflux
EEG*
Ca+ influx
GLU release
NT release
(Hall ’92)
Anoxic depolarization ↑ tyrosine hydroxylase
(Carmen & Wyatt ’77)
(Balestrino ’95)
+ activation of intraneuronal
catabolic enzymes (Choi ’89)
Cell swelling
(Balestrino ’95)
↑ DA production
+ uncouples oxidative
phospholiration in brain
mitochondria
(Kirsch ’89)
↓ breakdown in ATP
dependent transporters
(↓ NT reuptake)
5-HT3
NE
(Pulsinelli & Duffy ’83)
↓ ATP production
(Kirsch ’89)
↓ activity of O2dependent COMT
(Gibson ’81)
NH4+
Activation of
NMDA-receptors
(Felipo et al ‘98)
↑ cytotoxic quinones
(Graham ’78)
DA
As high as 500-fold
(Globus ‘88)
Substance Abuse
& Withdrawal
Critical Illness
Age & Hypoxemia
Isolation &
ICU Environment
Theorized Neurochemical Mechanisms Associated With Conditions
Leading To Delirium
Modified from Maldonado 2008, Critical Care Clinics(Maldonado 2008)
Delirium
Source
ACH
DA
GLU
GABA
5HT
NE
Trp
Phe
His
Cytok
Anoxia/hypoxia
#
$
$
#
#
#
$?
$
$,#
╬$
HPA
axis
╬
Aging
#
╬$
╬
#
$
$
$
$
#?
$
$
╬
╬
Sleep deprivation
Trauma, Sx,
Chages
in RBF
╬
EEG
╬
#
Mel
#
#
$?
$
$
$
╬
$?
#
$
$
#
$
#
$?
$?
#
$
$
$
$
Cort
╬
$
#
#
╬,#
╬
$
╬
#
#
$
$

$
#
╬
#
Inflam
$
$
CVA
Hepatic Failure
NMDA
activity
$
& Post-op
Etoh & CNS-Dep
Withdrawal
DA agonist
Infection/Sepsis
#?
GABA use
#
Dehydration &
Electrolyte
Imbalance
Medical Illness
#?
Hypoglyemia
#
#
$
#
╬
$
╬
#
#
#
$
$
╬
╬
$
$
#
$
$
$
╬
$
#
╬
#
$
╬
╬
#
Legend: $ = likely to be increased or activated; # = likely to be decreased;  = no significant changes; (╬) = likely a contributor, exact mechanism is unclear;
(-) = likely not to be a contributing factor; CVA = cerebro-vascular accident; Sx = surgery; Etoh = alcohol; CNS-Dep = central nervous system depressant agent;
ACH = acetylcholine; DA = dopamine; GLU = glutamate; GABA = gamma-aminobutyric acid; 5HT = 5-hydroxytryptamine or serotonin; NE = norepinephrine;
Trp = tryptophan; Phe = phenylalanine; His = histamine; Cytok = cytokines; HPA axis = hypothalamic-pituitary-adrenocortical axis; NMDA = N-methyl-Daspartic acid; RBF = regional blood flow; EEG = electroencephalograph; Mel = melatonin; Inflam = inflammation; Cort = Cortisol.
Schematic Representation of the Effects of
Alcohol Exposure & Withdrawal
Short-term alcohol intake produces a depression of the inhibitory centers of the cerebral cortex, which results
in the initial symptoms of intoxication (euphoria, exaggerated feelings of well-being, and loss of self-control
followed by sedation). Long-term alcohol intake causes the initial decrease with tolerance that occurs during
continued exposure to alcohol. Removal of alcohol causes a rebound stimulatory effect, increasing excitability
in the nervous system.
Adapted from Finn and Crabbe 1997
Acute&ETOH&Use&
•  GABA:%produces&allosteric&enhancement&of&GABAa&receptors;&
contribu<ng&to&many&aspects&of&acute&alcohol&intoxica<on,&
including&anxietyAreduc<on,&seda<on,&and&motor&incoordina<on.&&&
Alcohol&poten<ates&GABAa&receptor&signaling&by&increasing&the&
frequency&of&channel&opening&events,&mean&open&<me,&open&<me&
percentage,&frequency&of&opening&bursts,&and&the&mean&burst&
dura<on.&Acute&alcohol&exposure&also&enhances&the&release&of&
GABA&from&the&presynap<c&neuron,&thus&increasing&GABA&levels&in&
the&synap<c&cleE&and&further&ac<va<ng&the&hypersensi<ve&
extrasynap<c&receptors.%
•  GLU:&inhibits&NMDA,&AMPA,&kainate&&&Metabotropic&GLU&
receptors.&NMDA&receptors&are&the&most&sensi<ve&to&alcohol&
inhibi<on.&Modula<on&of&glutamatergic&func<on&by&ethanol&
contributes&to&both&euphoric&and&dysphoric&consequences&of&
ethanol&intoxica<on.&GLU&plays&a&significant&role&in&all&phases&of&
alcoholism.&
Acute&ETOH&Use&
•  DA:%Disinhibit&GABAAmediate&DA&projec<ons&to&VTA→↑DA&ac<vity&
by&direct&excitatory&DA&VTA&neurons&&&facilitates&DA&release&by&
increasing&opioidergic&ac<vity,&further&disinhibi<ng&DA&neurons,&
which&further&↑extracellular&DA&ac<vity&in&NA&(likely&responsible&
for&impulse&to&drink).&
•  NE:&Plasma&and&CSF&NA&and&its&major&metabolite&3AmethoxyA4A
hydroxy&phenylethylene&glycol&(MHPG)&are&increased&by&alcohol&
intoxica<on.&
•  CA+%Ch:%inhibits&voltageAgated&Ca+&channels&
•  5HT:%there&is&a&doseAdependent&increase&in&5HT&neurotransmission,&
in&par<cular&in&NA,&during&acute&alcohol&intake→&ac<vates&the&
mesolimbic&dopaminergic&reward&system,&further&adding&to&the&
reinforcing&ac<ons&of&the&alcohol.&
Acute&ETOH&Use&
•  HPA2axis:&is&ac<vated&during&alcohol&intake&via&cor<cotrophinA
releasing&factor&(CRF)&to&release&cor<sol&and&is&important&in&
media<ng&the&con<nued&urge&to&drink;&glucocor<coids&alter&
mesolimbic&dopaminergic&signaling,&thus&further&amplifying&the&
posi<ve&reinforcing&effects&of&ETOH&
•  MEL:%acute&alcoholAinduced&doseAdependent&a_enua<on&of&pho<c&
phaseAdelay&shiEs&and&serotonergic&phaseAadvance&shiEs,&where&
suprachiasma<c&nucleus&clock&was&demonstrated&to&be&a&direct&
target&for&disrup<ve&effects&of&ethanol&on&pho<c&shiEing&
Pathophysiology of Ethanol
Maldonado et al, in Press
AgonisCc%effect%at%GABAA%receptors%
Disinhibits%GABA2mediated%DA%projecCons%to%NA%→%DA%→%
↑%extracellular%DA%in%NA;%contribuCng%to%impulse%to%drink%
Acute
ETOH
Inhibits%GLU%receptors%
↑%of%NE%&%its%metabolite%with%acute%intoxicaCon%
InhibiCon%of%voltage2gated%Ca+%channels%
Dose2dependent%increase%in%5HT%neurotransmission%
AcCvaCon%of%HPA%via%CRF%→%release%corCsol;%mediaCng%the%
conCnued%urge%to%drink;%and%altering%mesolimbic%dopaminergic%
signaling,%further%amplifying%posiCve%reinforcing%effects%of%
ETOH%
AVenuaCon%of%phoCc%phase2delay%shiWs%and%disrupCon%of%
melatonin%release%cycle%%
Chronic&ETOH&Use&
•  GABA:%chronic&alcohol&use&leads&to&counteradapta<ve&responses&
that&decrease&GABA&func<on.&This&is&evident&by&both&a&decrease&in&
the&number&of&receptors&and&in&changes&in&subunit&composi<on&
that&decrease&receptor&sensi<vity.&&Prolonged&enhancement&leads&
to&desensi<za<on&of&GABAa&receptors,&internaliza<on&and&downA
regula<on&of&GABAa&receptors,&especially&in&frontal&lobes;&also&
causes&GABAa&rec&to&shiE&their&composi<on&to&contain&more&α4&
subunits,&a&forma<on&that&is&less&responsive&to&GABA&signaling&.&
Desensi<za<on&of&the&GABAA&receptor,&produced&aEer&chronic&
ethanol&treatment,&may&be&a&necessary&altera<on&that&allows&
ac<va<on&of&the&NMDA&receptors.&&
Chronic&ETOH&Use&
•  GLU:%increased&synap<c&glutamate&(GLU)&release;&increased&NMDA&
and&nonANMDA&(e.g.,&AMPA,&kainate&receptors)&glutamatergic&
receptor&ac<vity;&Chronic&exposure&of&the&brain&to&ethanol&leads&to&
upAregula<on&of&the&NMDA&receptor&and&its&responses&and&
increases&the&number&of&glutamate&binding&site.&
•  DA:%Chronic&alcohol&has&been&shown&to&cause&a&lowering&in&the&
basal&and&s<mulated&dopamine&signal;&with&associated&increased&in&
DA&availability.&&
•  NE:%In&addi<on,&chronic&ethanol&exposure&leads&to&over&ac<vity&of&
NE&neurons&in&the&central&and&peripheral&nervous&systems&via&
desensi<za<on&of&α2&receptors&or&lack&of&&α2&agonist&ac<vity&and&
excessive&NE&produc<on,&as&the&excess&extracellular&DA&is&converted&
into&NE&via&DAAßAhydroxylase.&&
Chronic&ETOH&Use&
•  Ca+%Ch:%↑&voltageAgated&Ca&channels&receptor&ac<vity.&
•  5HT:%Chronic&use&leads&to&downAregula<on&of&5HT1A&receptors&in&
hippocampus.&Decreased&expression&of&5HT2&receptor&genes&in&
cerebral&cortex&and&decreased&5HT&uptake.&
•  HPA2axis:%With&chronic&alcohol&use,&HPA&axis&becomes&dysregulated&
as&a&result&of&ini<al&superAexcita<on&with&the&repeated&intoxica<ons&
leading&to&loss&of&a&normal&diurnal&secre<on&pa_ern&and&
hyporeac<vity&in&cor<sol&response&to&physical&and&psychological&
stressors.&&
•  MEL:%Inversion&of&the&circadian&with&abnormally&elevated&diurnal&
levels&of&melatonin&
ETOH&Withdrawal&
•  GABA:%CSF&examina<on&reveal&that&GABA&levels&are&low.&chronic&
exposure&to&alcohol&produces&many&changes&in&the&neurotransmission,&
leading&to&an&overall&reduced&sensi<vity&to&inhibitory&signaling.&The&
need&for&an&increasing&amount&of&alcoholic&poten<a<on&in&order&to&
maintain&an&inhibitory&tone&creates&a&hyperexcitable&state&within&the&
central&nervous&system.&Symptoms&of&alcohol&withdrawal&are&due&to&
this&hyperexcitable&state,&including&an&increase&in&anxiety&and&seizures.&&&
While&benzodiazepines&are&the&primary&therapeu<c&agent&used&to&
enhance&GABA&func<on&during&the&hyperexcitable&state&of&alcohol&
withdrawal,&it&is&of&li_le&use&on&benzodiazepineAinsensi<ve&GABAa&
receptors.&&DesensiCzaCon%of%the%GABAA%receptor%can%also%contribute%
to%acCvaCon%of%the%NMDA%receptors.%The&reduc<on&in&GABAergic&
neuronal&transmission&and&a&rise&in&glutamatergic&transmission&during&
alcohol&withdrawal&may&lead&to&CNS&hyperexcita<on&leading&to&the&
development&of&agita<on&&&seizures.%
ETOH&Withdrawal&
•  DA:%DA&levels&on&AWSAD#1&have&been&correlated&with&the&severity&
of&AWS&as&measured&by&CIWAAscores&and&pharmacological&Tx&
needed.&Upon&AWS,&excess&DA&leads&to&confusion,&psychosis&
(hallucina<on,&illusions,&delusions),&agita<on,&delirium.&Data&shows&
that&pa<ents&with&DTs&demonstrated&significantly&higher&plasma&
HVA&than&the&control&group,&immediately&preceding&development&
of&their&psycho<c&symptoms.&
•  GLU:%An&increased&NMDA&receptor&func<on&is&observed&in&chronic&
alcohol&exposure,&which&produces&a&hyperexcitable&state&in&alcohol&
withdrawal.&There&is&a&direct&rela<onship&between&the&increased&
NMDA&receptorAchannel&complexes&and&the&symptoms&of&AWS,&
par<cular&AWSz.&Upon&AWS,&excess&GLU&leads&to&confusion,&
psychosis&(hallucina<on,&illusions,&delusions),&agita<on,&delirium&
and&seizure&ac<vity.&
ETOH&Withdrawal&
•  NE:%Circula<ng&levels&of&catecholamines&are&markedly&elevated,&
leading&to&increases&in&cardiac&output,&stoke&volume,&and&oxygen&
consump<on.&Human&studies&have&confirmed&that&CSF&levels&of&3A
methoxyA4Ahydrophenylglycol&(MHPG)&were&increased&in&pa<ents&
undergoing&alcohol&withdrawal.&Eleva<on&in&plasma&freeAMHPG&
concentra<on&may&similarly&play&a&role&in&the&evolu<on&of&delirium&
from&nonAalcohol&withdrawal.&ETOH&inhibits&the&sensi<vity&of&
autonomic&adrenergic&systems,&with&a&resul<ng&upAregula<on.&During&
AWS,&excess&noradrenergic&ac<vity&leads&to&the&development&of&
symptoms&of&autonomic&hyperac<vity&(e.g.,&anxiety,&agita<on,&tremor,&
swea<ng,&hypertension,&and&tachycardia).&↑[NE}&triggers&neuronal&
damage&by&inducing&imbalances&btw&cerebral&O2&demand&&&supply→&
↑sensi<vity&of&pyramidal&neurons&to&excitatory&effect&of&GLU&&&↓&
perfusion.&Also&↑NE→↑GLU.&Increased&NA&levels&may&aggravate&
hypomagnesaemia&(see&above),&thus&producing&another&posi<ve&
feedback&loop.&
ETOH&Withdrawal&
•  Ca+%Ch:%There&is&upregula<on&of&dihydropiridineAsens<ve&LAtype&
calcium&channels&during&the&acute&withdrawal&phase&further&
leading&to&propaga<on&of&the&excita<on&cascades.&&
•  5HT:%serotonergic&transmission&appears&to&be&decreased&possibly&
leading&to&the&dysphoria&of&alcohol&withdrawal&and&alcohol&cravings&
•  HPA:%HPA&axis&is&ac<vated&once&again&during&the&alcohol&
withdrawal,&leading&to&glucocor<coid&eleva<on,&par<cularly&in&
prefrontal&cortex&and&hippocampus,&further&poten<a<ng&the&
damage&resul<ng&from&alcohol&withdrawal.&Glucocor<coids&
modulate&ethanol&withdrawal&by&exacerba<ng&the&glutamatergic&
cascade,&possibly&via&ac<va<on&of&glucocor<coid&receptors&or&
increased&number/func<on&of&NMDA&receptors.&
•  MEL:%worsening&of&melatonin&&&circadian&cycle&reversal&
Pathophysiology of Ethanol
Maldonado et al, in Press
Acute%
ETOH%
Low%GABA%levels;%accompanied%by%↓GABAA%receptors%funcCon%
due%to%internalizaCon%and%↓%receptor%sensiCvity%
↑↑↑DA%leads%to%confusion,%psychosis%(hallucinaCon,%
illusions,%delusions),%agitaCon,%delirium%
↑↑↑NMDA%receptor2channel%complexes%acCvity%→%
hyperexicitable%state%of%AWS:%confusion,%psychosis%
(hallucinaCon,%illusions,%delusions),%agitaCon,%delirium%and%
seizure%acCvity.%
↑↑↑%%NA%acCvity%→SX%autonomic%hyperacCvity%(e.g.,%anxiety,%
agitaCon,%tremor,%sweaCng,%hypertension,%and%tachycardia).%
↑NA%→%↑GLU%&%triggers%neuronal%damage%by%inducing%
imbalances%btw%cerebral%O2%demand%→%↑sensiCvity%of%
pyramidal%neurons%to%excitatory%effect%of%GLU%
↑%voltage2gated%Ca+%channels→%propagaCon%of%the%
excitaCon%cascades%
Significantly%↓%5HT%neurotransmission→dysphoria%
↑↑↑%HPA%via%CRF%→%release%corCsol;%exacerbaCng%the%
glutamatergic%cascade%&%neuronal%damage%
Worsening%of%melatonin%&%circadian%cycle%reversal%
ETOH%NeuromodulaCon%
Maldonado'et'al,'in'Press'
%
GABA% GLUr%
DA%
NE%
VGCC%
Ca+%
Ch%
5HT%
HPA%
(CRF)%
MEL%
NGF% Mg+%
Acute%%
↑&
↓&
↑&
↑&
↓&
↑&
↑&
↓&
↑&
↔&
Chronic%
↑&
↓&
↑&
↑&
↓&
↑&
↓&
↓&
↑↑&
↓&
↑&
↑↑&
AWS%
↓↓& ↑↑↑& ↑↑↑& ↑↑&
(up&to&
300%)&
↑↑& ↓↓↓& ↑↑↑& ↓&
Pathophysiology of Ethanol
Agonistic effect at GABAA receptors
ETOH
Disinhibits GABA-mediated
DA projections to NA → DA
Physical
of
Is likely responsible for
impulse Sx’x
to drink
W/D =
excessive sympathetic drive
Inhibits NMDA receptors
GABAA
Α2-Agonists
↑ extracellular DA in NA
Adaptive suppression of GABA activity
(internalization and down-regulation receptors)
Desensitization of
α2 receptors or
inhibits the sensitivity of autonomic adrenergic
lack of α2 agonist
systems, with a resulting up-regulation
activity*
(DA-ß-hydroxylase)
NE
APA
Confusion, psychosis
ETOH
(chronic
consumption)
Maldonado 2009
(hallucination, illusions, delusions),
DA
↑ extracellular DA in NA
agitation, delirium
Is likely responsible for impulse to drink
GLU/NMDA
↑ GLU transmission to NA
Li et al ‘01
Dependence
Seizures
AntiGLU-ACA
up-regulation & hypersensitization of NMDA receptors
Alcohol Withdrawal
Assessment Scale (AWSS)
Clinical Institute Withdrawal
Assessment for Alcohol (CIWA-Ar)
Somatic (S) Subscale: Somatic symptoms
Score →
0
1
2
3
Pulse rate/
min
<100
101 – 110
111 – 120
>120
Diastolic BP
(mmHg)
<95
96 – 100
101 – 105
>105
Temperatur
e (°C)
<37.0
37.0 – 37.5
37.6 – 38.0
>38.0
Respiratory
rate/min
<20
20 – 24
>24
Perspiration
None
Mild
(wet hands)
Moderate
(forehead)
Severe
(profuse)
Tremor
None
Mild
(arms raised
& finger
spread)
Moderate
(fingers
spread)
Severe
(spontaneous)
Total
↓
Subscore of somatic symptoms →
Mental (M) Subscale: Mental symptoms
Score →
0
1
2
3
4
None
Fastening
Rolling in
bed
Try to leave
bed
In rage
Short talk
possible
Easily
distractible
Drifting
contact
Dialogue
impossible
Orientation
(time, place,
person,
situation)
Fully
aware
One sphere
disturbed
Two spheres
disturbed
Totally
confused
Hallucinatio
ns
None
Uncertain
One kind
present
Two kinds
present
Anxiety
None
Mild (only
if asked)
Severe
(spontaneous
complaint)
Agitation
Contact
All kinds
Subscore of mental symptoms →
Total score T = S + M →
Mild
Moderate
Severe
CIWA-Ar
AWSS
(Sullivan et al 1989; Shaw et al 1981; Hollbrock’99)
(wetterling et al 1997; 2006)
≤ 15
16-20
≥ 20
≤5
6–9
≥ 10
Total
↓
Patient
BAL
Non-benzo regimen
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6+
37 M
446
Clonidine / VPA / gabapentin
Dia 25 mg;
Lor 2 mg
Dia 50 mg;
lor 8 mg
Dia 10 mg
0
0
0
46 M
382
Clonidine / gabapentin
Lor 4 mg
Lor 2 mg
Clo 1 mg
Clo 0.5 mg
0
0
32 M
71.4
Clonidine / VPA
Lor 1 mg
Dia 30 mg;
lor 1 mg
Dia 15 mg;
lor 16 mg
Dia 5 mg;
lor 10 mg
Lor 2 mg
Day 6-10:
0
51 M
360
Clonidine / gabapentin
none
none
0
0
45 M
Not done
(prior
200s-300s)
Clonidine / VPA / neurontin /
Haloperidol
Dia 30 mg; lor
14 mg
Dia 35 mg;
lor 48 mg
Dia 40 mg;
lor 22 mg
Lor 2 mg
Lor 4 mg
0
58 M
367
Clonidine / VPA / neurontin
Dia 20 mg; lor 2
mg
Lor 2 mg
0
0
0
0
50 M
335
Dex / clonidine / VPA
Dia 5 mg; lor 2
mg; Dex ggt
Lor 2 mg;
off Dex
0
0
0
0
62 F
35 (prior
200s-300s)
Clonidine / gabapentin
Lor 4 mg
Lor 1 mg
0
0
0
0
66 F
47
Gabapentin
Lor 2 mg
none
Lor 1 mg
0
0
0
Dia 20 mg; lor 4 Dia 10 mg;
mg
lor 13 mg
Hair of the Dog:
Pathophysiology of Alcohol Withdrawal
& Foundations of Treatment
José R. Maldonado, M.D., FAPM, FACFE
Associate Professor of Psychiatry, Medicine, Surgery & Law
Scholar, Center for Biomedical Ethics
Stanford University School of Medicine
Stanford University School of Law
Chief, Medical & Forensic Psychiatry Section
Medical Director, Psychosomatic Medicine Service
Stanford University Medical Center
[email protected]